Cerebral dopamine neurotrophic factor-deficiency leads to degeneration of enteric neurons and altered brain dopamine neuronal function in mice

NEUROBIOLOGY OF DISEASE

卷:134

Article

Lindahl, Maria¹  Chalazonitis, Alcmene²  Palm, Erik¹  Pakarinen, Emmi¹  Danilova, Tatiana¹  Pham, Tuan D.²  Setlik, Wanda²  Rao, Meenakshi^2,5  Voikar, Vootele³  Huotari, Jatta¹  Kopra, Jaakko⁴  Andressoo, Jaan-Olle^1,6,7,8  Piepponen, Petteri T.⁴  Airavaara, Mikko¹  Panhelainen, Anne¹  Gershon, Michael D.²  Saarma, Mart¹ 

[1] Univ Helsinki, Inst Biotechnol, HiLIFE Unit, Viikinkaari 5D, FI-00014 Helsinki, Finland

[2] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA

[3] Univ Helsinki, Lab Anim Ctr, Neurosci Ctr, Mustialankatu 1, FI-00014 Helsinki, Finland

[4] Univ Helsinki, Fac Pharm, Div Pharmacol & Pharmacotherapy, Viikinkaari 5E, FI-00014 Helsinki, Finland

[5] Harvard Med Sch, Boston Childrens Hosp, Div Gastroenterol, Boston, MA USA

[6] Univ Helsinki, Fac Med, POB 63, Helsinki 00014, Finland

[7] Univ Helsinki, Helsinki Inst Life Sci, POB 63, Helsinki 00014, Finland

[8] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, SE-17177 Solna, Sweden

关键词: Cerebral dopamine neurotrophic factor (CDNF);    Knockout mouse;    Enteric nervous system;    Midbrain;    Dopaminergic;    Dopamine transporter;    Neurodegeneration;    Autophagy;    Parkinson's disease;   

DOI  :  10.1016/j.nbd.2019.104696

来源: Elsevier

【 摘 要 】

Cerebral dopamine neurotrophic factor (CDNF) is neuroprotective for nigrostriatal dopamine neurons and restores dopaminergic function in animal models of Parkinson's disease (PD). To understand the role of CDNF in mammals, we generated CDNF knockout mice (Cdnf(-/-)), which are viable, fertile, and have a normal life-span. Surprisingly, an age-dependent loss of enteric neurons occurs selectively in the submucosal but not in the myenteric plexus. This neuronal loss is a consequence not of increased apoptosis but of neurodegeneration and autophagy. Quantitatively, the neurodegeneration and autophagy found in the submucosal plexus in duodenum, ileum and colon of the Cdnf(-/-) mouse are much greater than in those of Cdnf(+/+) mice. The selective vulnerability of submucosal neurons to the absence of CDNF is reminiscent of the tendency of pathological abnormalities to occur in the submucosal plexus in biopsies of patients with PD. In contrast, the number of substantia nigra dopamine neurons and dopamine and its metabolite concentrations in the striatum are unaltered in Cdnf(-/-) mice; however, there is an age-dependent deficit in the function of the dopamine system in Cdnf(-/-) male mice analyzed. This is observed as D-amphetamine-induced hyperactivity, aberrant dopamine transporter function, and as increased D-amphetamine-induced dopamine release demonstrating that dopaminergic axon terminal function in the striatum of the Cdnf(-/-) mouse brain is altered. The deficiencies of Cdnf(-/-) mice, therefore, are reminiscent of those seen in early stages of Parkinson's disease.